title: A PEGylated analog of the gut hormone oxyntomodulin with long-lasting antihyperglycemic, insulinotropic and anorexigenic activity.
abstract: Peptide agonists of the glucagon-like peptide 1 (GLP-1) receptor (GLP1R) are rapidly gaining favor as antidiabetic agents, since in addition to increasing glucose-dependent insulin secretion, they also cause weight loss. Oxyntomodulin (OXM), a natural peptide with sequence homology to both glucagon and GLP-1, has glucose-lowering activity in rodents and anorectic activity in rodents and humans, but its clinical utility is limited by a short circulatory half-life due to rapid renal clearance and degradation by dipeptidyl peptidase IV (DPP-IV). Here, we describe the development of a novel DPP-IV-resistant, long-acting GLP1R agonist, based on derivatization of a suitably chosen OXM analog with high molecular weight polyethylene glycol (PEG) ('PEGylation'). PEG-OXM exerts an anti-hyperglycemic effect in diet-induced obese (DIO) mice in a glucose-dependent manner, with a maximally efficacious dose of 0.1mg/kg, and reduces food intake and body weight with a minimally efficacious dose of 1mg/kg. If this pharmacology is recapitulated in patients with type 2 diabetes, these results indicate PEG-OXM as a potential novel once-weekly GLP-1 mimetic with both glucose-lowering activity and weight loss efficacy.
authors.affiliation: IRBM P. Angeletti, 00040 Pomezia, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bianchi
authors.forename: Paul E
authors.initials: PE
authors.lastname: Carrington
authors.forename: Paolo
authors.initials: P
authors.lastname: Ingallinella
authors.forename: Marco
authors.initials: M
authors.lastname: Finotto
authors.forename: Alessia
authors.initials: A
authors.lastname: Santoprete
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Petrov
authors.forename: George
authors.initials: G
authors.lastname: Eiermann
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kosinski
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pocai
authors.forename: Ranabir
authors.initials: R
authors.lastname: SinhaRoy
authors.forename: Antonello
authors.initials: A
authors.lastname: Pessi
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D053772:Oxyntomodulin / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011323:Primates; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism
chemical_list: D001067:Appetite Depressants; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D053772:Oxyntomodulin; D018027:Receptors, Glucagon; D011092:Polyethylene Glycols
keywords: Diabetes; GLP-1 receptor agonist; Incretin; Obesity; Oxyntomodulin; PEG